Autoimmune uveitis is a debilitating and potentially blinding inflammatory disease that affects 93 in 100,000 Americans annually. The current treatment strategy is to control the inflammation with immunosuppressive medication that include steroids, which in turn have serious side effects, such as cataracts, glaucoma, peptic ulcers, bone decalcification, and systemic susceptibility to infection. A mouse model of human autoimmune uveitis, experimental autoimmune uveitis (EAU) has been used to better understand this disease. In contrast to chronic human uveitis, EAU resolves without intervention and mice are resistant to recrudescence of uveitis because of regulatory immunity found in the spleen. This regulatory immunity requires post-EAU Treg cells to be activated by post-EAU antigen presenting cells (APC). We have shown that the melanocortin 5 receptor (MC5r) is required for the emergence of a regulatory APC in the post- EAU spleen, and this regulatory APC is a source of adenosine that activates the post-EAU Treg cell through the adenosine 2A receptor (A2Ar). This is an interesting finding, because these two pathways have been shown to individually regulate immunity, but our observation is the first to link the two pathways. The result of stimulating this melanocortin-adenosinergic pathway is an autoantigen specific Treg cell that suppresses EAU. This focus of this proposal is how these Treg cells function to suppress inflammation (Specific Aim 1), if reactivation requires contact dependent factors, and how long-lasting the Treg cells are (Specific Aim 2). Stimulation of MC5r or A2Ar during EAU effectively suppresses disease and induces regulatory immunity. Therefore, it may be possible to stimulate these pathways to induce regulatory immunity and suppress human autoimmune uveitis. In this proposal we will translate our mouse findings into the clinic by assaying for the induction of regulatory immunity on human PBMC from chronic uveitis patients following stimulation of the melanocortin-adenosinergic pathway (Specific Aim 3). Our hypothesis is that the melanocortin-adenosinergic pathway induces effective and long-term regulatory immunity. We propose to combine murine studies with a translational study to answer important mechanistic questions about ocular autoantigen specific Treg cells and to bring these findings into the clinic to develop a uveitis treatment that provides lasting remission.